In vitro studies show that antitumor activity can be enhanced when cytotoxic drugs are used in combination. This has led, over the years, to the use of drug combinations in the clinic such that cytotoxic drug combinations are now standard in many forms of cancer chemotherapy. New anticancer drugs are typically first introduced in patients as single agents. After a maximum tolerated dose is determined for one agent, a second agent is added and the dose of one or both agents is adjusted on the basis of toxicity. The development of these combination regimens then is determined empirically on the basis of tolerability. However, in vitro, where the ratio of drugs used in combination can be controlled, it has been demonstrated that drug combinations providing synergy at one ratio may be simply additive or even antagonistic at other ratios (Mayer, L. D., et al., Mol. Cancer Ther. (2006) 5:1854-63; Chou, T-C., et al., Adv. Enzyme Reg. (1984) 22:27-55). When individual free drug is administered, each agent is handled differently by the body, resulting in varying distribution of the individual drugs to tumor sites which can result in drug ratios that are sub-optimal or ineffective. Consequently, in vitro synergistic activity of antineoplastic drugs often depends on specific drug ratios, and the in vivo activity of a combination therefore depends on maintaining a synergistic or additive ratio and avoiding antagonistic ratios. In this way, the development of a particular chemotherapeutic regimen can be based on the most efficacious ratio rather than empirically based on toxicity.
Fluoropyrimidines have been the cornerstone for the treatment of advanced colorectal cancer for over 30 years. 5-fluorouracil (5-FU) is regarded as standard systemic chemotherapy for this indication (Van Laar, J. A. M., et al., Eur. J. Cancer (1998) 34:296-306, Coutinho, A. K., et al., Cancer Control (2003) 10:224-238). Response to 5-FU appears to correlate with inhibition of thymidylate synthase activity more so than with incorporation of 5-FU into RNA. For this reason, intravenous floxuridine (the deoxyribonucleoside derivative of 5-FU) was investigated clinically in the early 1960's with the hypothesis that it would be therapeutically superior to 5-FU (Young, C. W., et al., Cancer Chemother. Repts. (1960) 6:17-20, Ansfield, F. J., et al., Cancer Chemother. Repts. (1963) 32:101-105, Reitemeier, R. J., et al., Cancer Chemother. Repts. (1965) 44:39-43, Eastern Cooperative Group, JAMA (1967) 200:101-118). These studies were conducted at leading oncology centers utilizing protocols that were state of the art at the time. Although Floxuridine clearly had activity in these studies, there was no clinical evidence that 5-FU and Floxuridine were meaningfully different. Floxuridine did not appear to be more active than 5-FU. 5-FU was less difficult to manufacture and more available so except for certain clinical investigations (Creaven, P. J., et al., Cancer Chemother. Pharmacol. (1994) 34:261-265), 5-FU has been used most often for systemic therapy. Floxuridine has demonstrated activity when administered as an hepatic arterial infusion in patients with hepatic metastases and is approved for this indication in the US (Anonymous, J. Natl. Cancer Inst. (1996) 88:252-258, Kemeny, N., et al., Lancet Oncol. (2001) 2:418-428).
Since the approval of irinotecan in 1996, the combination of irinotecan plus 5-FU has become a standard chemotherapy for first and second line treatment of metastatic colorectal cancer. The current most popular regimens are FOLFIRI as well as irinotecan as a single agent. Irinotecan is usually administered in two ways. In one regimen, 350 mg/m2 irinotecan IV over 30 minutes administered every 21 days (Rougier P., et al., J. Clin. Oncol. (1997) 15:251-60). In another regimen, 125 mg/m2 irinotecan IV over 90 minutes on days 1, 8, 15 and 22 repeated every 42 days (Pitot H. C. et al., J. Clin. Oncol. (1997) 2910-19). FOLFIRI usually contains about irinotecan 180 mg/m2 IV, leucovorin (LV) 100-500 mg/m2, and 5FU 2300-3000 mg/m2 to be administered intravenously (IV) in 24 or 48 hour infusion or 400 mg/m2 bolus followed by 600 mg/m2 22 hour infusion on days 1 and 2 repeated every two weeks. IFL contains irinotecan at 70 or 125 mg/m2, LV 20-200 mg/m2, and 5FU 450-500 mg/m2 for IV bolus administration weekly for 4 weeks followed by two weeks rest. IFL is less favored because it is potentially more toxic and somewhat less active than FOLFIRI.
Despite the advantages associated with the use of combined drug cocktails, there are various drawbacks that limit their therapeutic use. For instance, administration of free drug cocktails often results in rapid clearance of one or all of the drugs before reaching the tumor site. If the individual drugs in the cocktail are only optimally effective within a narrow ratio to one another, a rapid clearance of one drug but not the other can reduce overall efficacy of the combination while often increasing toxicity. This can sometimes lead to increased toxicity as individual drug dosages are increased to achieve a greater therapeutic effect. Fluoropyrimidines such as 5-FU and floxuridine exhibit such rapid elimination and consequently attempts to improve activity have utilized longer infusion times to improve efficacy and toxicity profile of these agents. Typical times for such infusional administration can range from 24 hours or longer. Thus, drug delivery regimens that permit the sustained administration of an optimized drug combination ratio is highly desirable as its will permit reduced administration times without increasing the toxicity of the treatment. Such improvements in regimens also may permit higher overall doses being administered to the patient than would be possible with other regimens that are limited by toxicity.